The glycosylation of cellular proteins and lipids is an integral part of many normal cellular functions, yet glycosylation, including sialylation, may also contribute to tumor cell formation, metastasis, and invasion. Sialylation is catalyzed by a family of sialyltransferases (STs) that transfer sialic acid, a nine-carbon amino sugar that is negatively charged under physiological conditions, to the terminal position of growing oligosaccharide chains of glycoconjugates. Hypersialylation plays a vital role in cellular adhesion, immune defense, and inflammation, yet altered ST activity is also implicated in tumor formation and invasion in many tumor models (Harvey et al., 1992; Majuri et al., 1995; Dall'Olio and Chiricolo, 2001; Wang et al., 2002). And specifically, the α sub-type ST, α-2,3-sialyltransferase (α-2,3-ST), is up-regulated by overexpression of the ras oncogene (Easton et al., 1991). The identification of potent ST inhibitors, therefore, represents a promising approach to the development of cancer therapies, including therapies directed at preventing metastasis.
A number of ST inhibitors have been developed. These include inhibitors with a structural mimetic of transition-state analogues, bisubstrate analogues, donor analogues, and acceptor analogues based on cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac) or disaccharides (Skropeta et al., Glycoconjugate J., 2004, 21:205; Chang, Tao and W.-S. Li, Synlett, 2004, 37; Whalen, McEvoy and Halcomb, Bioorg. Med. Chem. Lett., 2003, 13:301; Schwoerer and Schmidt, J. Am. Chem. Soc., 2002, 124:1632; Muller, Schaub and Schmidt, Angew. Chem., Int. Ed., 1998, 37:2893). Although these compounds effectively inhibit STs, they display poor permeability across cell membranes and thus their clinical applications are limited. Similarly, ST inhibitors purified from natural products are available in only small quantities, limiting their availability for clinical use (Hsu et al., 2005).
It is accordingly an object of the present invention to provide novel lithocholic acid analogues and pharmaceutical compositions comprising these lithocholic acid analogues that potently inhibit α-2,3-ST and display improved membrane permeability for cellular uptake. It is a further object of the present invention to provide α-2,3-ST inhibitors that treat a disease responsive to inhibition of α-2,3-ST activity.